The present invention provides methods for treatment of psychological conditions. Such psychological conditions, including major depression, hypomania, cyclothymia, anxiety, bipolar disorder, insomnia and other sleep disorders, hyperactivity, attention deficit disorder, chronic fatigue syndrome, premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), and agoraphobia, take an enormous toll on people's ability to work, maintain relationships, communicate effectively, think properly, perform physical activity, and sense the environment around them.
The most common of these psychological conditions is depression, which ranks first among all causes of disability in the United States and second after heart disease, as a cause of healthy years lost to premature mortality and disability (Regier et al., Arch Gen Psychiatry 45:977 (1988). Depression can be divided into several types. Major depression is the most severe form of depression characterized by a severe, persistent depressed mood and loss of interest or pleasure in normal activities accompanied by decreased energy, changes in sleep habits, restless behavior, difficulty concentrating, loss of appetite, feelings of guilt or hopelessness, and in severe cases, psychotic symptoms such as hallucinations, delusions, and even suicidal thoughts. An individual must have a history (greater than 2 weeks) of persistent sad moods, loss of interest or pleasure in activities once enjoyed, and feelings of guilt or hopelessness, restless behavior, difficulty concentrating, and even suicidal thoughts in order to make a diagnosis of major depression. The Beck's Depression Scale Inventory, or other screen tests for depression, can be helpful in diagnosing depression.
Major depression can be treated with medications and/or counseling. Studies have shown that antidepressant drug therapy combined with psychotherapy appears to have better results than either therapy alone (Elkin et al., Arch Gen. Psychiatry 46:971 (1989). Medications used include, but are not limited to, tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin re-uptake inhibitor (SSRIs), and some new antidepressant drugs such as bupropion, reboxetine, trazodone, venlafaxine, and mitrazapine. Antipsychotic medications are needed for patients suffering from more severe forms of psychotic symptoms, such as delusions or hallucinations. Types of psychotherapy that have proven to be particularly effective for treating depression include interpersonal therapy, group therapy, and cognitive/behavioral therapy. Often experimenting with the right combination of these drugs and therapy is required by the treating physician. Unfortunately, up to 30% of patients with major depression do not gain substantial benefit from initial antidepressant treatments. Often, it is recommended that if one drug does not improve the mood of a patient after 4-6 weeks of treatment, the drug should be changed (Potter et al., N. Eng. J. Med. 325:633 (1991)). Finally, electroconvulsive therapy (ECT), which is a treatment that causes a central nervous system seizure by means of an electric current, is often reserved as a treatment of last resort, in order to improve the mood of severely depressed or suicidal people who do not respond to other treatments. ECT, however, is accompanied by severe side effects, such as long-lasting memory impairment (Hyman et al., Merks Manual of Medicine, Chapter 13 page 13 (2000)).
Alternative therapeutic methods include the use of herbal products for management of chronic conditions, such as psychiatric disorders, including anxiety and depression. In addition, St. John's Wort (hypericum) has recently gained popularity as an adjunct antidepressant in the United States. The National Institute of Health has recently sponsored a Hypericum Clinical Trial comparing 50 to 150 mg/day of sertraline (Zololoft), 900 to 1800 mg/day of St. John's Wort, and placebo in 300 patients with major depression. The conclusion of the study was St. John's Wort was no more effective for treating major depression of moderate severity than a placebo (NIH News Release, Apr. 9, 2002). Side effects of St. John's Wort are mild and primarily include gastrointestinal symptoms and fatigue. Therefore, there is a need in the art for alternative treatments, which are more effective and are associated with fewer side effects for treating major depression.
A second form of depression is chronic low-grade depression, also known as dysthymia. Dysthymia is present most of the time for a period of two or more years wherein an individual experiences a decrease in his/her overall level of energy, appetite, and sleep, as well as has feelings of low self-esteem and hopelessness. These symptoms cause distress and the individual has difficulty functioning in everyday activities. These symptoms, however, are not as severe as those symptoms experienced in major depression. The cause and maintenance of these symptoms are often due to one of the following problems: loss of a friend, substantial disappointment at work or home, prolonged or chronic illness, and alcohol or drug abuse. People who suffer from dysthymia are at an increased risk for episodes of major depression. This produces a behavioral pattern called “double depression,” wherein the individual is mildly depressed most of the time, with periodic symptoms of major depression.
Treatments for mild depressive disorders include improving health habits like acquiring adequate, regular sleep and good nutrition. Also, decreasing the use of alcohol and other drugs and becoming involved in healthy activities such as recreation and creative endeavors will relieve depressed feelings. In cases where a subject is unable to shake these “depressed” feelings within a few weeks, the subject may be suffering from major depression and should contact their physician.
The least severe form of depression is a depressed mood. This is an emotional state dominated by feelings of sadness, gloominess, or emptiness, which may be associated with lack of energy. Depressed moods are usually temporary responses to an unhappy or stressful event. Treatments for such conditions are the same as discussed above in treatments for mild depressive disorders.
Finally, diagnosis of depression is different for the different stages in one's life. Elderly depression is one such example. Elderly patients, who present excessive concerns about bodily aches and pains, fatigue, loss of appetite, and sleeping difficulties, are demonstrating, in reality, secondary affects of depression. Depression in the elderly is infrequently diagnosed and untreated due to the fact many older individuals do not admit to the signs or symptoms of depression. Depression in adolescents also requires careful examination. For example, physical examination is used to rule out other medical causes for depressive symptoms. Careful psychiatric evaluations are required to assess the history of the persistent sad, empty, or irritable state of the adolescent patient, along with obtaining information about whether other family members have a history of depression.
Bipolar Disorders
Bipolar disorder is a chronic disease affecting over 2 million Americans at some point in their lives. Bipolar disorder affects men and women equally and appears between the ages of 15 and 25. As opposed to unipolar major depression, the incidence of biopolar disorder does not vary widely around the world. The exact cause is unknown, but it is linked to areas of the brain which regulate mood, and has a strong genetic component. The American Psychiatric Association's “Diagnostic and Statistical Manual of Mental Disorders” describes two types of biopolar disorder, type I and type II. In type 1 (formerly known as manic depressive disorder), there has been at least one full manic episode. People with this type, however, may also experience episodes of major depression. In type II disorder, periods of “hypomania” involve more attenuate (less severe) manic symptoms that alternate with at least one major depressive episode. When the patients have an acute exacerbation, they may be in a manic state, depressed state, or mixed state. The manic phase is characterized by elevated mood, hyperactivity, over-involvement in activities, inflated self-esteem, a tendency to be easily distracted, and little need for sleep. In the depressive phase, there is loss of self-esteem, withdrawal, sadness, and a risk of suicide. Either the manic or the depressive episodes can predominate and produce a few mood swings, or the patterns of the mood swing may be cyclic. While in either phase, patients may abuse alcohol or other substances, which worsens the symptoms.
Methods for treating bipolar disorders differ depending upon the state of the patient. During an acute phase, hospitalization may be required to control the symptoms. In order to reduce the risk of switching into mania, hypomania or rapid cycling, a combination of a mood stabilizer (e.g. lithium; valproate) and antidepressants (e.g., bupropion) is effective for controlling bipolar disorders. Even though lithium is effective in controlling manic and depressive relapses, careful medical supervision along with maintaining salt intake, avoiding nonsteroidal anti-inflammatory drugs, and undertaking weight-reduction diets are all required in order to reduce possible renal failure. Valproate also is characterized by severe side effects including nausea, vomiting, anorexia, heartburn, and diarrhea. Finally, the use of antidepressants for suppressing bipolar disorder must also be carefully monitored in order to achieve full symptomatic remission. Therefore, safer therapeutic methods are needed in the art in order to reduce the severe side effects associated with current treatments of bipolar disorders.
Cyclothymic disorders are similar to bipolar disorders, but less extreme. Cyclothymic disorders are characterized by stages of mild mood changes with stages of mild depression and excitement (hypomania). The changes in mood are very irregular and abrupt, but the severity of the swings is less. Cyclothymia is treated like biopolar disorders, though often not as aggressively. Thus, safer treatments are needed in the art.
Anxiety Disorders
Anxiety disorders, panic attacks, and agoraphobia are conditions that occur as a manifestation of primary mood disorders such as depression. Anxiety is a feeling of apprehension or fear that lingers due to an individual's perception of persistent and unrelenting stress. Anxiety is accompanied by various physical symptoms including twitching, trembling, muscle tension, headaches, sweating (e.g., night sweats), dry mouth, or difficulty swallowing. Some people also report dizziness, a rapid or irregular heart rate, increased rate of respiration, diarrhea, or frequent need to urinate when they are anxious. Fatigue, irritable mood, sleeping difficulties, decreased concentration, sexual problems, and nightmares are also common. Some people are more sensitive to stress and are thus more likely to develop anxiety disorders. The propensity to succumb to anxiety attacks may be due to genetic predisposition or by previous (e.g. childhood) exposure to certain stresses.
Treatment of anxiety disorders includes diagnostic tests for blood differential and thyroid function as well as an electrocardiogram (EKG). If any worrisome physical signs or symptoms do not accompany the anxiety, a referral to a mental health care professional is recommended. Psychotherapy such as cognitive-behavior therapy (CBT) along with the medication benzodiazepines, which facilitate the actions of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the nervous system, are the most effective in severe cases of anxiety. In addition to these treatments, use of antidepressants such as imipramine and the selective serotonin re-uptake inhibitor (SSRI) paroxetine have been shown to produce antianxiety benefit to anxiety patients (Rocca et al., Acta Psychiatr Scand 95:444 (1997)). Treatment with benzodiazepines, however, is accompanied by fatigue, drowsiness, and unsteadiness. After successive treatments with benzodiazepines, patients often develop dependence to the drug and, therefore, careful medical monitoring is required. Thus, there is a need in the art for treatments that provide less drug dependence along with a reduction in side effects and costs.
Panic disorder, one of the anxiety disorders, is characterized by repeated and unexpected attacks of intense fear and anxiety. Panic attacks are usually not related to a particular situation and typically “peak” within ten minutes of their onset. The exact cause of panic disorder is unknown, but it is associated with multiple physiological factors. Panic disorder can occur with or without agoraphobia, but agoraphobia develops in one-third of cases. Agoraphobia is a disorder characterized by avoidance of crowds, and open and public places, particularly if escape or assistance is not immediately available. The development of agoraphobia may involve learned behavior, since it reflects a fear of experiencing panic attacks in unprotected settings, and sometimes the association of panic attacks with areas where they have occurred. The prevalence rate of panic attacks in the population is as high as 1.5 to 5% (Cruz, et al). Panic disorder can occur in children, but the average age of onset is 25 years old. Panic disorder affects middle-aged and older adults as well. Studies have shown that women are 2 to 3 times more likely to be affected (Cruz, et al.).
Symptoms of panic disorder include shortness of breath, dizziness, palpitations, trembling, sweating, choking, nausea, numbness, chest pain, hot flashes or chills, fear of dying, fear of losing control, and fear of going insane. Symptoms of agoraphobia include anxiety about being in places where escape might be difficult, fear of being alone, fear of losing control in a public place, feeling of helplessness, and feelings of detachment. Treatments for both disorders are similar to treatment of anxiety. Antidepressant medicines are effective for treatment of many people with panic disorder and agoraphobia including SSRIs such as Paxil. Behavior therapies are also used in conjunction with drug therapy including relaxation techniques, pleasant mental imagery, and cognitive behavioral therapy to restructure distorted and harmful interpretations of particular situations. As discussed above, the disadvantage of these therapies is possible drug dependence, harmful side effects, and costs. Therefore, there is a need in the art to develop novel methods for treating panic disorders and agoraphobia.
Premenstrual Syndrome (PMS)
Woman's physical, emotional, and behavioral changes associated with phases of their menstrual cycle may worsen mental disorders such as depression and bipolar disorder (discussed below). These changes are referred to as premenstrual syndrome (PMS). In some women, these changes occur regularly, are sometimes severe, and are characterized as feelings of depression, irritability, and other emotional and physical changes. These changes typically begin after ovulation and become gradually worse until menstruation starts. PMS is estimated to affect 70% to 90% of women during their childbearing years. Thirty to forty percent of women suffer from PMS symptoms severe enough to interfere with daily living activities. Wide ranges of physical and emotional symptoms are associated with PMS. By definition, such symptoms must occur during the second half of the menstrual cycle (14 days or more after the first day of the menstrual cycle) and be absent for about 7 days after a menstrual period ends. Symptoms of PMS include, but are not limited to the following: headache, swelling of ankles, feet, and hands, backache, abdominal cramps, breast tenderness, weight gain, bloating, anxiety, confusion, depression, forgetfulness, irritability, fatigue, low self-esteem, and paranoia.
Current treatments for PMS include self-care methods such as exercise and dietary measures wherein nutritional supplements such as vitamin B6, calcium, and magnesium are used. In addition, prostaglandin inhibitors may be prescribed for women with significant pain including headache, backache, menstrual cramping, and breast tenderness. Diuretics can be prescribed for women found to have significant weight due to fluid retention. Psychiatric medications and/or therapy may be used for women who exhibit a moderate to severe degree of anxiety, irritability, or depression. Finally, oral contraceptives may decrease PMS symptoms. Although these treatments provide relief to most women, more effective treatments that eliminate or reduce side effects and costs are still needed in the art.
Premenstrual Dysphoric Disorder (PMDD)
An estimated 3-4% of women suffer severe premenstrual mood symptoms that significantly interfere with work and social functioning. These severe premenstrual symptoms are diagnosed as premenstrual dysphoric disorder (PMDD) or mid-cycle dysphoria. The occurrence of PMDD is higher in women in their late 20s and early 40s, those with at least one child, those with a family history of major depression disorder, or women with a past medical history of either post-partum depression or an affective mood disorder. PMDD differs from PMS in that prospective premenstrual mood symptoms described above occur across multiple menstrual cycles rather than the latter half of the menstrual cycle. Adequate diagnosis is important, because PMDD symptoms may be severe enough to prevent women from maintaining normal function. These symptoms, combined with a patient already suffering from depression, place these patients at a significantly higher risk of committing suicide during the latter half of their menstrual cycle.
Treatments for PMDD include hormone agonist therapy (gonadotropin-releasing hormone (GNRH) agonist leuprolide), and serotoninergic antidepressant therapy (clomipramine, fluoxetine, sertraline, and citalopram). These therapies have demonstrated efficacy in controlling PMDD, but require continuous pharmacotherapy throughout the menstrual cycle, which increases the side effects and costs of these treatments. Intermittent treatments of PMDD with medication administered daily only during the luteal phase (e.g. for 14 days premenstrually) is being studied, but at present has not been implemented. Thus, there is a need in the art for a therapeutic method for treating PMDD and PMS wherein the side effects and costs are reduced and continuous pharmacotherapy is not required.
Other Psychological Disorders
Attention Deficit Disorder (ADD) is the most commonly diagnosed psychological disorder of childhood, affecting 3% to 5% of school aged children. Symptoms include developmentally inappropriate levels of attention, concentration, activity, distractibility, and impulsivity. There are three sub-categories of attention deficit disorder: (1) attention deficit/hyperactivity disorder of the combined type; (2) attention deficit/hyperactivity disorder of the predominantly inattentive type; and (3) attention deficit/hyperactivity disorder of the predominantly hyperactive or impulsive type. Despite much progress in the diagnosis and treatment of ADD, the treatment for this disorder remains highly controversial. While the cause of attention deficit disorder is unknown, scientists have determined a neurological basis for the disease and genes have been identified that are thought to be involved in ADD.
The most effective treatment strategy for ADD is using psychotropic medications such as Dexedine (dextroamphetamine), Ritalin (methylphenidate), and Cylert (magnesium pemoline). Antidepressants (such as amitriptyline or fluoxetine), tranquilizers (such as thioridazine), alpha-adrenergic agonist (clonidine), and caffeine have also been tried to treat ADD. The disadvantage of these drugs is the lack of long term information on the affect these drugs have on the cognitive and emotional development of ADD children. In addition, medications such as antidepressants, tranquilizers, and caffeine have met with little success. A significant amount of research has been carried out studying psychological therapeutic treatments such as contingency management (e.g. time out), cognitive-behavioral treatment (e.g. self monitoring, verbal self instruction, problem solving strategies, and self reinforcement), parent counseling, and individual psychotherapy. Studies using these techniques have yielded mixed results and no studies have been carried out combining psychological interventions with stimulant medications. Therefore, parents are directed to manage the symptoms and direct the child's energy to constructive and educational paths.
Exacerbations of Depression or Other Psychological Conditions
If untreated, depression or other psychological conditions can lead to further complications over a period of time directly dependent upon the severity of depression or psychological condition. There is usually an increased risk of problems with physical and emotional health, which can lead to premature death due to an accentuated medical illness. In turn, physical and emotional maladies such as chronic fatigue syndrome, constipation, tension headaches, and various sleep disorders perpetuate the depressive state of an individual (along with anxiety and bipolar disorders). Depression also increases the risk of tobacco dependence and/or alcohol abuse and/or drug-related problems. Finally, risk of committing suicide is increased up to as much as 15% of those people who suffer from depressive disorders such as major depression. Therefore, there is a need in the art for more improved treatments of depression, which will lead to improvement of other physical, emotional, and substance abuse maladies and vice versa.
Sleep Disorders
Another secondary effect of depression and other psychological conditions is sleep disorders. A sleep disorder is a disruptive pattern of sleep that may include difficulty falling or staying asleep, falling asleep at inappropriate times, excessive total sleep time, or abnormal behaviors associated with sleep. There are more than 100 different disorders of sleeping and waking. They can be grouped into four main categories: problems with staying and falling asleep (insomnia, e.g.), problems with staying awake (sleep state misperception, e.g.), problems with adhering to a regular sleep schedule (hypersomnias such as narcolepsy, e.g.), and sleep disruptive behaviors (sleep walking, e.g.). Both insomnia and sleep disruptive behaviors could be direct results of a patient suffering from a psychological disorder such as depression or anxiety.
Insomnia includes any combination of difficulty with falling asleep, staying asleep, intermittent wakefulness, and early-morning awakening and can lead to the following disorders: psychophysiological, delayed sleep phase syndrome, hypnotic dependent disorder, and stimulant dependent sleep disorder. Episodes may be either transient (2-3 weeks) or chronic. Common factors associated with insomnia are depression, anxiety, stress, illness, caffeine, abuse of alcohol, medication, illness, physical discomfort, and counterproductive sleep habits such as early bedtimes and daytime napping. Treatment of insomnia is related to the cause. If there is an obvious physical or psychological cause (such as depression), it is the first focus of treatment.
Sleep disruptive behaviors include sleep terror disorder, sleep walking or REM behavior disorders (a type of psychosis related to lack of REM sleep and lack of dreaming). Symptoms of sleep disruptive behaviors are depressed mood, anxiety, apathy, difficulty concentrating, irritability, daytime fatigue, drowsiness, and difficulty falling asleep. Again, treatment of sleep disruptive behaviors is often related to the cause. If there is an obvious physical or psychological cause, it is the first focus of treatment.
Tension Headaches
A tension headache is one of the most common forms of headache. It can occur at any age, but is most common in adults and adolescents. If headaches occur two or more times weekly for several months or longer, the condition is considered chronic. Tension headache is a result of contraction of the neck and scalp muscles. One cause of this muscle contraction is a response to stress, depression, or anxiety. Any activity that causes the head to be held in one position can cause a headache. Other causes include eye-strain, fatigue, alcohol use, excessive smoking, excessive caffeine use, or conditions such as sinus infection, nasal congestion, overexertion, colds, influenza, etc. Tension headaches are not associated with structural lesions in the brain. Current treatment is aimed at relieving symptoms and preventing reoccurrence of the headache. Stress management is one such treatment aimed at removal and control of precipitating factors such as anxiety or depression. There is a need, however, in the art for more effective treatments for tension headaches.
Chronic Fatigue Syndrome
Chronic fatigue syndrome is a condition of prolonged and severe tiredness and weakness (fatigue) that is not relieved by rest and is not directly caused by other conditions. Recent studies have shown that chronic fatigue syndrome may be caused by inflammation of pathways in the nervous system; and that this inflammation may be some sort of immune response or autoimmune process. Chronic fatigue syndrome may occur when a viral illness is complicated by an inadequate or dysfunctional immune response. Other factors such as age, prior illness, stress, environment or genetic disposition and depression may also play a role in the disease. Although depression is indirectly related to chronic fatigue syndrome, it may contribute to the unusual nervous system symptoms associated with this disease. Many people with chronic fatigue syndrome experience depression and other psychological problems that may improve upon treatment. There is no current treatment that has proven to be effective in curing chronic fatigue syndrome. Some proposed treatments are antiviral drugs, medications to treat depression, medications to treat anxiety, and medications to treat pain, discomfort, and fever. Even though depression and anxiety may not be directly linked to chronic fatigue syndrome, depression and other psychological disorders are intricately interrelated with this disease and, therefore, there is a need in the art to find new innovative ways for treating these diseases.
Constipation
Constipation is a relative term. When the stool is hard, infrequent, and requires significant effort to pass, the person has constipation. Constipation may cause discomfort with passage of stools, and passage of large, wide stools may tear the mucosal membrane of the anus, especially in children, causing bleeding and the possibility of an anal fissure. Constipation can be caused by changes in diet, decrease in physical activity, diseases of the bowel, congenital diseases, medications, dehydration, behavior and psychological problems such as depression and anxiety, and neurological diseases. Depression and anxiety are again aggravating factors that contribute to a person suffering from constipation. There is a need in the art to focus on treatment of the depression or anxiety disorder in order to overcome the secondary effects of conditions like constipation.
A patient is considered to have chronic (long duration) constipation if (1) for at least 12 months, patients not taking laxatives report two or more of the following: fewer than three bowel movements per week; excessive straining during at least 25% of bowel movements; passage of hard or pelletlike stool during at least 25% of bowel movements; a feeling of incomplete evacuation for at least 25% of bowel movements; or (2) for at least 12 months, patients have an average of fewer than two bowel movements per week.
Cravings
Substance-related disorders appear to be caused not by a single agent but by a combination of social, biological, and psychological factors. Stress can serve as an inducement for craving or addictive behavior, especially chronic stress, and with continued or repeated use of the substance in question, a dependency of physiological and/or psychological origin. Simple habituation can be complicated by a growing dependency, especially if the substance craved provides a sense of happiness or pleasure via the dopamine or other pathway. Often depression is thought to be a prelude to craving or dependence, although it has likewise been argues that craving leads to depression.
Regardless of origin, craving reflects a biochemical process which, in theory, if interrupted could lead to correction of the malady by regulating those bio-active molecules associated with addiction pathways in such a manner as to restore relative homeostasis at a molecular, or sub-molecular level. Accordingly, there remains a desire for methods and compositions for the treatment of cravings.
Nerve Growth Factor
Nerve growth factor (NGF), a prototypical neurotrophic factor and member of the neurotrophin family, promotes a wide range of responses in target cells. These responses include, but are not limited to, neuron differentiation, maintenance of neuronal survival, and regulation of metabolic activities. Nerve growth factor is well-characterized neurotrophic factor that is essential for the normal development and function of basal forebrain cholinergic neurons in the central nervous system (CNS) (Ghahn et al., 1983; Thoenen and Edgar, 1985). A central area of research in application of nerve growth factor has been its application to age-related cognitive impairments due to the atrophy or loss of basal forebrain cholinergic neurons (Armstrong et al., Neurobiol. Aging 14:457-470 (1993)). For example, studies have shown the intraventricular infusion of NGF can reduce cholinergic neuron atrophy and improve spatial learning or memory retention in aged rats (Scali et al., Neurosci Lett 170:117-120 (1994); Markowska et al., J. Neurosci 14:4815-4825 (1994)). Due to studies indicating decreased immunoreactivity for the NGF receptor in basal forebrain of aged rodents, neural growth factor appears to be linked to spatial learning and memory retention (Fischer et al., Neurobiol. Aging 13:9-23 (1992)). One example of therapeutic uses of NGF includes administering NGF to patients with senile dementia of the Alzheimer's type (SDAT). The problem of such treatment is NGF does not pass through the blood-brain barrier in physiologically relevant amounts and treatments required intracranial surgery (Kordower et al., Exp. Neurol. 124:21-30 (1993). Novel carrier systems consisting of NGF covalently linked to an anti-transferrin receptor antibody (OX-26) have been able to cross the blood-brain barrier.
Despite these recent applications of nerve growth factor, there remains a desire to use NGF to remedy other neurological disorders. Moreover, there exists a growing concern over the widespread use of psychotropic drugs for treating disorders such as depression, anxiety, bipolar disorder. Accordingly, there remains a desire in the art for improved treatment of various psychological conditions by administration of safer compounds that are relatively inexpensive, safe without accompanying side effects, and that can easily be administered.